Discovery, Optimization, and Evaluation of Selective CDK4/6 Inhibitors for the Treatment of Breast Cancer

Breast cancer is the most common tumor in women, and
selective
cyclin-dependent kinase (CDK) 4/6 inhibitors played an important role
in the treatment of breast cancer. Therefore, discovering selective
CDK4/6 inhibitors with great safety and potent efficacy is beneficial
for the breast cancer treatment. In our work, the lead compound 8 was identified through virtual screening; then, systematic
structural optimization was conducted to afford 42, which
exhibited strong inhibition on CDK4/6 and showed high selectivity
among 205 kinases. 42 possessed excellent safety profiles
(LD50 > 5,000 mg/kg), favorable pharmacokinetic properties
(F % = 43%), and potent efficacy in reducing the
burden of breast cancer in vivo. In conclusion, we offered a highly
selective CDK4/6 inhibitor, which could be used as a great candidate
for further preclinical studies of breast cancer.

乳腺癌是女性最常见的肿瘤，选择性周期素依赖性激酶（CDK）4/6抑制剂在乳腺癌治疗中发挥了重要作用。因此，发现具有卓越安全性和高效力的选择性CDK4/6抑制剂对乳腺癌治疗大有裨益。在本次研究中，通过虚拟筛选确定了先导化合物8；随后，我们对化合物进行了系统的结构优化，得到了化合物42，该化合物对CDK4/6表现出强大的抑制活性，并在对205种激酶的筛选中显示出高度的选择性。化合物42具有良好的安全性特征（LD50 > 5,000 mg/kg）、有利的药代动力学特性（F% = 43%）以及在体内显著降低乳腺癌负担的强大疗效。综上所述，我们提供了一种高度选择性的CDK4/6抑制剂，可作为乳腺癌进一步临床前研究的优秀候选药物。